Hematologic toxicity is a principal cause of morbidity and mortality after exposure to ionizing radiation (IR). G-Zero Therapeutics, with operations in the Research Triangle Park, North Carolina, has developed a novel approach to mitigating the hematologic toxicity of total body irradiation (TBI). This approach relies on the administration of novel, orally bioavailable small molecule kinase inhibitors around the time of exposure to TBI. These compounds in turn induce pharmacological quiescence (PQ) of the early hematopoietic stem and progenitor cells (HSPC) through the inhibition of cyclin dependent kinases (CDK's) which govern the G1-S transition of the cell cycle. As quiescent cells are resistant to IR, PQ enhances the per cell survival of HSPC by augmenting the repair of DNA damage post-TBI. This enhanced survival of HSPC in turn translates into markedly reduced acute hematologic toxicity. G-Zero has shown in mice that the PQ approach can significantly boost the tolerated dose of IR when administered at the time of TBI (dose modifying factor >1.3). Additionally, CDK inhibitor administered 20 hours after TBI still affords significant radioprotection with enhanced animal survival, and we anticipate that time of administration can be extended to more than 24 hours post exposure. As little as a single oral dose of kinase inhibitor affords radioprotection, enhancing survival and protecting all blood lineages including red cells, platelets, granulocytes and lymphocytes. G-Zero has licensed broad intellectual property surrounding the use of PQ for radioprotection. In this proposal, we seek to extend these results in three specific aims. In aim 1, we will test several additional CDK small molecule inhibitors with differing pharmacokinetics in vitro and in vivo to identify the optimal dosing schedule for maximal radioprotection. In aim 2, we will perform extensive characterization in rodents of the pharmacology and toxicology of the most promising CDK inhibitors identified in aim 1. In aim 3, we will additionally determine the ability of PQ to afford protection against the long-term sequelae of peri-lethal doses of IR. We believe these Phase I studies will position G-Zero to begin primate studies of CDK inhibitors in Phase II. It is our expectation that this work will lead to a simple and non-toxic pill that will enhance survival when taken up to 24 hours after a peri-lethal IR exposure that could occur as a result of nuclear accident or radiological attack. PUBLIC HEALTH RELEVANCE: Exposure to radiation from terrorist attack and resulting toxicity is an imminent threat to the American public and military. Hematological toxicity through radiation-induced DNA damage of blood-producing cells of the bone marrow is a severe lethal consequence of radiation exposure of humans. G-Zero Therapeutics is developing drugs which can be stockpiled and easily administered following such an attack to protect the bone marrow from the damaging effects of radiation.